Page 1 of 22 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION MEMORANDUM Date: May 2 7 , 2011
SUBJECT: DCPA
. (Chlorthal Dim ethyl). Human Health Assessment Scoping Document in Support of Registration Review.
PC Code: 07 87 01 DP Barcode: 386 63 7 Decision No.: 4 4489 5 Registration No. : Not Applicable Petition No.: Not Applicable Regulatory Action: Registration Review Scoping Risk Assessment Type: Not Applicable Case No.: 0 2 7 0 T XR No.: Not Applicable CAS No.: 1861

- 32

- 1 MRID No.: None 40 CFR: 180. 1 8 5

FROM: Christine L . Olinger, Risk Assessor

Kit Farwell , D. V.M. , Toxicologist Jeffrey L

. Dawson, Chemist Risk Assessment Branch VII Health Effects Division (7509P) Office of Pesticide Programs
THRU: Michael S. Metzger, Chief,

Risk Assessment Branch VII Health Effects Division (7509P) Office of Pesticide Programs
TO: Jill Bloom

Risk Management and Implementation Branch I II Pesticide Re

- evaluation Division (7508P) Office of Pesticide Programs
Executive Summary The Health Effects Division (HED) DCPA (dimethyl tetrachlorophthalate) R egistration Review T eam has evaluated the most recent human health assessments and database for the herb icide DCPA to determine the scope of work necessary to support the established tolerances and existing regi strations. The risk assessment used to support the 199 8 Reregistration Eligibility Decision (RED) and a risk assessment to support new tolerances of DCPA (Dole, 2004) were the primary sources for this evaluation. DCPA is registered for use on several vegetable crops and some ornamental plants. Most residential uses have been cancelled and are no longer supported by the primary

registrant.Page 2 of 22

Liver and th yroid effects are observed in many DC PA toxicity studies. The acute toxicity of DCPA is low

. Toxicity

in longer term studies with DCPA included thy roid toxic ity as shown b y decreased level s of thy

roid hormone, microscopic thy roid changes, and increased thy roid weight. Liver toxicity

included increased liver weight, elevated liver enz ym e activity , increased cholesterol, and liver h yp ertroph y. It is believed that the liver effects are precursor events to the thy roid effects, with increased metabolism of thy roid hormone by

the liver resulting in a compensatory

stimulation of the thy

roid. Effects on the kidney have also been observed . There were no mutagenicity

c oncerns for DCPA , but thyroid follicular cell adenomas/carcinomas, hepatocellular adenomas/carcinomas, and hepatocholangiocarcinomas were found in rats ; hepatic adenomas were found in mice. DCPA is classified a Group C, possible human carcinogen with a cancer potency factor based on the three combined liver tumors in female rats. DCPA has not been identified as a member of a common mechanism group for cumulative risk assessment. The previous risk assessment identified a 28

- day inhalation toxicity study and a comparative thy roid toxicity study

as data gaps. These studies are still required. The test guidelines have been updated since the 2002 assessment and additional studies are now required, including i mmunot oxicity

and acute and subchronic neurotoxicity studies. The endpoints and the FQPA safety factor will be re

- evaluated after these studies have been completed and reviewed. The most recent dietary , residential, aggregate, and occupational risk assessments did not identify risk estimates of concern. It is noted that DCPA and its environmental degradates are often found in groundwater monitoring studies. Additional residue chemistry studies are needed to support the registration review of DCPA including rotational crop field trials , sample storage information from prior crop field trials, a ruminant feeding study , a poultry metabolism study , and a livestock method validation. These studies had been previously requested in the RED and in respons e to new tolerances established in 2004. A new poultry feeding study

is reserved pending results of the metabolism study

. Once these studies have been received and reviewed, a new dietary

assessment will be conducted to support the registration review of DCPA. Since the residential uses are no longer supported a new residential assessment will not be needed. However several studies have been identified in the literature that describe off

- target movement of DCPA into residential settings, particularl y in agricultural areas. The Agency will evaluate these studies during registration review to determine if a quantitative assessment of risk to residents in agricultural areas is needed. Should new points of departure for dermal and inhalation routes of expo sure be identified once the new toxicity studies are received, a revised occupational assessment may be required. There are impurities of toxicity concern in DCPA formulations. Prior assessments have estimated risks from exposure to these contaminants, and have determined them to be negligible. During registration review the registrants should certify that the impurities in current formulations are at similar levels or below the levels previously assessed. If not, then a new assessment may

be required.Page 3 of 22

Introduction DCPA (dimethyl tetrachlorophthalate) is also commonly referred to as dacthal, chlorthal dimethyl or chlorthal methyl. DCPA is a chlorinated benzoic acid herbicide which inhibits cell division of root tips in target plants. It controls many annual grasses and broadleaf weeds in a variety of agricultural crops and ornamental varieties (e.g., broccoli, onions, tomatoes, cabbage, cauliflower, dogwood, azalea). Annual agricultural use from 1998 through 2008 averaged approximately

500,000 pounds over 100,000 acres with broccoli and onions accounting for 79 percent of that use (Ratnayake, 2011) . Information also suggests that on average 50 percent of broccoli is treated and 15 percent of onions (SLUA) . It was also reported that use for ornamental crops in nurseries is low at around 2,600 pounds in 2006. California usage data exhibit similar trends for the ye ars 2006

- 2008 (CA Usage reference)

. Most uses in residential settings have been cancelled and the remaining residential uses are not support ed, so will eventuall y be removed (personal communication, J. Bloom, 3/3/11). Tolerances are established in 40 CFR § 180. 185 for residues of DCPA , which address direct treatment of crops as well as inadvertent residues of DCPA from off

- target movement and carryover of residues to rotational crops. The metabolites monomethyltetrachloroterephthalate (MTP) and tetrachloroterephthalic acid (TCP or TPA ) are included in the tolerance expression for DCPA. Codex has not established maximum residue limits (MRL s) but MRL s are established in Canada for several commodities. The HED DCPA Registration Review Team evaluated the most recent human health assessments and database for DCPA to determine the scope of work necessary to support Registration Review. In addition, HED has conducted a screening literature search for studies that could contribute to the assessment. T he Reregistration Eligibility Decision (RED) and associated chapters as well as a risk assessment to support new tolerances were the primary so urces for this document

. Itshould also be noted that previous assessments assessed risks from trace contaminant materials in DCPA products.

Hazard Identification/ Toxicology Toxicity of DCPA : The database for DCPA is extensive. P revious risk assessment s considered subchronic and chronic oral studies in rats, subchronic and chronic oral studies in mice, developmental studies in rats and rabbits, a 2

- generation reproduction study in rats, a dermal toxicity study in rats, metabolism studies, a de rmal absorption study , and a battery of mutagenicity

studies with DCPA. Since the previous risk assessment, the registrant has conducted subchronic rat and dog studies and a chronic dog study with DCPA. These studies have been reviewed and will not result in changes to previously selected endpoints for DCPA. The previous risk assessment identified an inhalation toxicity study and a comparative thy roid study as data gaps. These studies are still required. The test guidelines have been updated since the 2002 assessment and additional studies are now required, including immunotoxicity and acute and subchronic neurotoxicity studies.Page 4 of 22

The acute toxicity

of DCPA is low. DCPA is in acute toxicity category I II for the oral route of exposure and is in toxi city category IV for dermal and inhalation routes of exposure. It is a mild irritant to the eyes and skin and it is not a skin sensitizer. Toxicity in longer term studies with DCPA included thy roid toxic ity

as shown by

decreased level s of thy

roid hormo ne, microscopic thy roid changes, and increased thy roid weight. Liver toxicity included increased liver weight, elevated liver enzy me activity , increased cholesterol, and liver h ypertroph y. Itis believed that the liver effects are precursor events to the thy roid effects, with increased metabolism of thy roid hormone by

the liver resulting in a compensatory stimulation of the thy

roid. Other toxicity

included anemia, pneumonitis, and kidney toxicity (increased kidney

weight, increased incidences of chronic nephropathy , and changes in clinical pathology). A PubMed search was conducted and no new toxicity information which would result in changes to the previous risk assessment was found. There were no mutagenicity concerns for DCPA. Thy roid follicular cell adenomas/carcinomas, hepatocellular adenomas/carcinomas, and hepatocholangiocarcinomas were found in rats ; hepatic adenomas were found in mice. DCPA was classified a Group C, possible human carcinogen , with a cancer potency factor based on the three combined liver tumors in female rats of 1.5 x 10 - 3 (mg/kg/day) - 1

. FQPA Assessment : There were acceptable rat and rabbit developmental toxicity studies and an acceptable 2

- generation reproduction study . No quantitative or qualitative susceptibility occurred in these studies and no neurotoxicity was noted in any

of the studies. The F QPA s afety

factor for DCPA was reduc ed to 1X in the most recent risk assessment. Considering current policy for FQPA database uncertainty factors, the FQPA factor would likely be retained at 10x for the lack of a comparative thyroid study. The most recent risk assessment showed very

low risk estimate s, so retaining the 10x factor would not likely result in these estimates exceeding the level of concern. Toxicity Endpoints : The chronic dietary endpoint for DCPA was thy roid toxicity

with a NOAEL of 1 mg/k g/day

and a LOAELof 10 mg/kg/day from a chronic rat study

. The endpoint for incidental oral exposure and for inhalation exposure was hepatocellular hypertroph y with a NOAEL of 50 mg/kg/day and a LOAEL of 100 mg/kg/day from a subchro nic rat study . No appropriate endpoint for acute dietary exposure was identified in any of the toxicity

studies. Quantitation of dermal exposure was not required because no s ys temic toxicity occurred in the dermal toxicity

study at the high dose of 1000 mg/kg/day

. There were no concerns for developmental or reproductive toxicity by the dermal route of exposure because no developmental toxicity

occurred in the developmental studies and parental and offspring effects in the reproduction study (decreased body weight) occurred at the same dose. Although the thy roid was not evaluated in this study , no liver effects were noted and liver hy pertroph y is believed to be a precursor event for thyr oid changes. The endp oints and the FQPA safety factor will be re

- evaluated after completion of the inhalation, neurotoxicity, comparative thy roid toxicity , and immunotoxicity studies. Toxicity of Metabolites and Degradates : Also evaluated in previous risk assessments were subchronic oral studies, a developmental rat study, and mutagenicity studies with TPA, aPage 5 of 22

degradate found in water. The only effects occurring in these studies were irritation from the acid moiety

on this compound. Since the previous risk assessment, th e registrant has conducted a mutagenicity study

with MTP, which is a rat metabolite and environmental degradate

. This study has been reviewed and will not result in changes to conclusions in the previous risk assessment

. Conclusions: Additional toxici ty data are required , including a comparative thy roid toxicity study , an i mmunotoxicity study , and acute and subchronic neurotoxicity studies . Once these studies have been received and reviewed the Agency will evaluate the need for modifying endpoints for risk assessment and associated safety factors.
Dietary Exposure DCPA is registered for use on several vegetable crops; according to the use profile prepared b y BEAD the predominant uses are on broccoli and onions. The residue chemistry data was most re centl y reviewed in association with tolerances in/on several herbs (Hazel, 2002). Adequate plant metabolism, analy

tical method, crop field trial, and processing studies are available to support the existing uses. However, the following residue data gaps were identified in the most recent discussion of the residue database: (i) rotational crop field trials and labeling prop osals, including crops to be rotated and plant

- back intervals (P BIs); (ii) sample storage temperature and duration to confirm the stab ility of residues in samples collected and anal yz ed as part of certain field trials conducted prior to 1995; (iii) a ruminant feeding study ; (iv) a poultry metabolism study ; and (v) livestock method validation. Rotational crop field trials and storage stability data remain outstanding; the specific studies requiring stability data are listed in the W. Hazel memo of 2002. The acceptability of the existing poultry

feeding study

will be addressed once the poultry m etabolism study has been submitted and evaluated. It is noted that the previous technical registrant attempted to address some of these deficiencies in 2002 in MRIDs 43340401, 42713501, and 43938901. However, these studies were resubmissions of existing data and did not fully address the requirements. There is some concern for inadvertent residues of DCPA due to off

- site movement that appears to be largel y due to wind

- blown soil particles to which DCPA residues have adsorbed. HED has updated the maximum reasonable dietary burden for livestock in accordance with the guidance published in 2008. The maximum reasonable dietary burden ( MRDB ) for dairy cattle is 8 ppm; residues in edible livestock commodities are likel y, so the requ irement for the ruminant feeding study remains outstanding. An adequate poultry metabolism study is not available, and the existing feeding study for poultry has numerous deficiencies. Therefore, the previousl y required poultry

metabolism study

is still needed to assess potential exposure to DCPA residues in poultry commodities. A method validation for the livestock residue analy tical method remains outstanding. An updated summary of the MRDB may

be found in Table 3 of this document. PDP data are avail able for residues of DCPA on numerous commodities. Over the last several ye ars, quantifiable residues were found in/on broccoli, cantaloupe, cauliflower, green beans, green onions, collards, kale, lettuce, onion, potatoes, summer squash, and bell peppers. InPage 6 of 22

addition, residues have been detected occasionall y on commodities where no tolerances have been established. For example, during 2007 and 2008 5% of celery samples anal yz ed had detectable residues of DCPA per se at an average residue of 2.5 ppb, with residues ranging from 1.2 to 12 ppb (lowest LOD is 0.7 ppb). In addition in the years 2003, 2006, and 2008 2% of spinach samples have detectable residues of DCPA per se at average residue of 5.5 ppb, with residues ranging from 1.2 to 43 ppb (lowest LOD i s 0.7 ppb). No tolerances have been established on celery

and spinach. There are a large number of studies and data available on DCPA and degradate residues in air, surface water, drinking water, ground water, rain, and snow. The most recent review of m onitoring data was completed in May 2008 by the Office of Water (EPA, 2008) , and reported in detail in the 2009 California Red

- legged Frog risk assessment of DCPA. Monitoring data indicate widespread occurrence of DCPA in surface water, ground water, drinking water, and air. DCPA and TPA are among the most commonly found pesticides/degradates found i n water samples (U.S. EPA, 2008 ). DCPA is ty picall y detected at low concentrations in remote areas where it is not used and at higher concentrations near where it is used. DCPA's degradates, TPA and MTP are more commonly detected in ground water samples than DCPA. TPA is ty pically found at higher concentrations. TPA was the most commonly detected pesticide

- derived compound in the National Survey of Pesticid es in Drinking Wat er Wells Survey (U.S. EPA, 1998 ). The estimated chronic risk from residues of DCPA in food was well below the level of concern in the most recent risk assessment, with the highest population estimat ed at 1% of the cPAD. Cancer risk esti mates were in the range of 10 - 7 . Prior assessments did not directly include drinking water, but estimated environmental concentrations were well below the drinking water level of comparison indicating that no human health risk estimates of concern exist

. HED has also assessed dietary risks for the impurities of concern. Further discussion may be found in the appendix to this document. Conclusions . The following studies remain outstanding: (i) rotational crop field trials and labeling proposals (crops to be rotated and PBIs); (ii) sample storage temperature and duration to confirm the stability

of residues in samples collected and analyzed as part of certain field trials conducted prior to 1995; (iii) a ruminant feeding study ; (iv) a poultry metabolism study ; and (v) livestock method validation. The rationale for requiring these studies is attached to this document. Once these studies have been received and reviewed a new dietary risk assessment should be conducted. In addition, the registrants should certify that the impurity

levels previously

assessed in dietary

risk assessment have remained the same or decreased.
Residential Exposure Residential risks from DCPA use were considered in the previous assessments and the risk estimate s that were calculated were not of concern for the uses at the time and given the policies used to define them . A turf transferable residue study for DCPA and its impurities was used in this assessment . Since the existing assessments were completed, most residential uses have beenPage 7 of 22

deleted from most DCPA labels and the remaining residential uses are not supported, so will eventuall y b e removed (personal communication, J. Bloom, 3/3/11). It should be noted, however, that the Agency is considering how to evaluate risks associated with exposures that can occur from the off

- target movement of pesticide residues in agricultural areas. During the screening literature search EPA identified a few studies that quantify residues of DCPA in homes in agricultural areas (Bradman, Gunier, Har nley , etc.) so any

future changes in risk assessment policies regarding these exposures may require updated DCPA risk assessments. Conclusion s : No residential data gaps were identified during the Registration Review scoping process for DCPA. At this time residential uses of DCPA are not supported, so assessments are not needed in registration review. However , an assessment may be needed to address changes in other risk assessment policies related to spray drift , and volatilization of pesticides. This is especiall y germane since data exist that quantify some level of off

- target movement from treated areas into residential settings.
Aggregate Risk Assessment The most recent risk assessment included aggregate assessments that considered exposure from food, drinking water, and residential uses. All risk estimate s were below the level of concern. Risk estim ate s from the impurities were also considered, and were below the level of concern. A new assessment will likely be needed that considers the required new toxicity and residue data as well as changes in residential uses. In addition, the new assessment m ay need to consider changes that consider off

- target movement of pesticides into residential settings.

Cumulative Risk Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to DCPA and any

other substances. For the purposes of this registration revie w assessment of data needs EPA has not assumed that DCPA has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effe cts of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

. Occupational E xpos ure DCPA controls many

annual grasses and broadleaf weeds in a variety of agricultural crops and ornamental varieties (e.g., broccoli, onions, tomatoes, cabbage, cauliflower, dogwood, azalea). DCPA formulations include flowable concentrates and wettable powders. In agriculture, groundboom and aerial applications would be ty pical but DCPA can also be applied via chemigation and using handheld equipment, especially associated with the production of ornamental and nursery

crops
. Application rates can be as high as 10.5 pounds DCPA per acre. DCPA is marketed in ty

pical containers that would allow open mixing activities (e.g., bottle).Page 8 of 22

Applications can be made prior to planting, as a pre

- emergent, and as a layby treatment over existing crops. Concurrent cultivation practices are also recommended b y l abels to ensure efficacy of DCPA and reduce the potential for off

- site movement (e.g., soil incorporation, banding applications, and proper irrigation timing). Occupational risk estimate s from DCPA use were consid ered in the previous assessments. Current labels require the use of normal work clothing for handlers with gloves and dust/mist respirators. The current Restricted

- Entry Interval is 12 hours. Prior assessments were based on chemical

- specific dislodgeab le foliar residue studies. For all scenarios assessed, occupational risks were not of concern if these required label risk management elements were followed

. A revised occupational risk assessment will be required because updated monitoring data are bein g developed for pertinent occupational handler exposures and additional handler exposure scenarios also need to be addressed that were not included in previous assessments. These include aerial application and handheld methods used for the production of nursery and ornamental crops. Additionally , a revised risk assessment may be needed to address possible exposure to workers doing activities in previously treated areas (i.e., post

- application exposure). The existing policy

on farmworker activities was rec entl y revised and include s either updated values for quantitatively

evaluating these exposures or it will provide a more definitive qualitative rationale for not conducting a quant itative assessment. In the existing assessments a dermal noncancer endpoi nt was not identified for risk assessment purposes but cancer risks from dermal exposures were quantitatively assessed. Additionally , noncancer and cancer risks were quantified for occupational handler inhalation exposures. Finally , post

- application canc er risks from dermal exposures were quantified. Any changes in risk assessment endpoints for DCPA would necessitate appropriate revisions to the risk assessment. It should also be noted that there are trace contaminant materials in DCPA products which we re addressed in existing risk assessments , but they may require further review and anal ys is as part of the registration review process. Conclusions: No occupational data gaps were identified during the Registration Review scoping process for DCPA . Adequate data, including studies currentl y in progress by various task forces, are available to assess all of the occupational exposure scenarios for the registered uses of DCPA. It is noted that the primary registrants are members of the Agricultural Reentry Task Force (ARTF ), the Agricultural Handlers Exposure Task Force (AHETF) , and the Outdoor Residential Exposure Task Force (ORETF). It should also be noted that likely upcoming policy revisions such as anticipated modifications in the Agency policies for completing occupational exposures could cause elements of the current exposure assessments to be revised (e.g., possible changes in transfer coefficients for field workers and unit exposures for handlers). These changes could specifically occur based on the results of the ARTF , AHETF and ORETF. Also, additional scenarios may

be needed to address changes in other risk assessment policies related to spray drift, worker protection and volatilization of pesticides.Page 9 of 22

Public Health and Pesticide Epidemiology Data HED has reviewed the OPP Incident Data Sy stem (IDS) to determine if there were significant incidents related to DCPA and human health (Winfield, 2011). Based on the low frequency and severity of incident cases, there does not appear to be a concern at this time that would warrant further investigation of incidents involving DCPA

. The Agency will continue to monitor the incident information and if a concern is triggered, additional anal ys is will be included in the risk assessment.

Tolerance Assessm ent and International Harmonization The US has established tolerances crops with registered uses of DCPA as well as inadvertent residue tolerances resulting from indirect exposure to crops via carry

- over in the soil and transport of residues through drift. A summary of US tolerances may

be found in T able 2 attached to this document, al ong with a summary of Canadian M aximum Residue L imits (MRL)

. Codex has not established MRL s in/on any commodity , and Mexico generally ad opts US tolerances and/or Codex MRL s for export purposes. Note that the MRLregulations for Canada do not include a separate entry for inadvertent residues. The US and Canada are not harmonized with respect to residue definition: the US includes two met abolites (MPA and TPA) in the residue definition, while the Canadian MRL includes only the parent. With respect to residue levels, for almost all commodities where both US and Canadian limits have been established, the values are the same, with the exception of the Brassica vegetables. Whereas the US has established a crop group tolerance at a level of 5 ppm, Canada has established limits for the individual commodities, ranging from 1 to 5 ppm. Some of the entries for the section on inadvertent tolerance s include crops with registered uses. The registrants should clearl y indicate in their response to the Registration Review Preliminary Work Plan (PWP) those crops where direct applications will be supported, and those tolerances that will be supported as inadvertent tolerances. During registration review HED will re

- evaluate the data supporting the tolerances , correct the entries in the tolerance regulation , and will attempt to harmonize with international MRL s to the extent possible . In addition the res idue definition should be modified in accordance with current policy on tolerance definitions (S. Knizner, 5/27/09) as describe below: Tolerances are e stablished for residues of the herb icide dimethyl tetrachloroterephthalate (DCPA) , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only the sum of DCPA and its metabolite s monomethyltetrachloroterephthalate (MTP ) and tetrachloroterephthalic acid (TCP) , calculated as the stoichiometric equivalent of DCP A , in or on the commodity

.

Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations,"Page 10 of 22

http://www.epa.gov/environmentaljustice/resources/policy /exec_order_12898.pdf

. The Office of Pesticide Programs (OPP) ty pically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, in cluding, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S. (including different ages, regions, and ethnicities), and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

Human Studies Past DCPA risk assessments relied in part on data in generi c databases from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure or similar studies from the literature. Man y such studies, involving exposure to many different pesticides i ncluding DCPA, are included in generic pesticide exposure databases such as the Pesticide Handler Exposure Database (PHED), the Agricultural Reentry Task Force (ARTF), and the Outdoor Residential Exposure Task Force (ORETF)

. Also, there will be a reliance on the work of the Agricultural Handlers Exposure Task Force (AHETF) for revisions to the occupational handler risk assessments possibly needed in the future. These studies have been determined to require a review of their ethical conduct and have received the appropriate review.
Endocrine Disruption As required b y FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic t oxicity , including assessments of carcinogenicity , neurotoxicity , developmental, reproductive, and general or sy stemic toxicity

. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology , organ weights, estrus cyclicity , sexual maturation, fertility , pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, development al and reproductive effects in different taxonomic groups. As part of its reregistration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), DCPA is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate”

. The EDSP employ s a two

- tiered approach to making the statutorily

required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thy roid (E, A, or T) hormonal s ystems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based onPage 11 of 22

the available data. Tier 2 testing is designed to identify an y adve rse endocrine

- related effects caused b y the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 20 10, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. DCPA was included on that list and has been issued an order to conduct the Tier 1 testing. Once all requ ired Tier 1 and Tier 2 data have been received and reviewed, the endpoints and safety factors used for risk assessment purposes will be examined and a new risk assessment performed if necessary . For further information on the status of the EDSP, the polic ies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/.
Data Requirements The following studies are required to support the registration review of DCPA: Toxicity studies

 870.7800 : Immunotoxicity
 870.3700SS (Special Study) : Comparative Thy roid Study
 870.3465 : Subchronic Inhalation Toxicity Study

– 28 day
 870.6200: Neurotoxicity Battery (Acute and Subchronic Studies) Residue Chemistry

S tudies

 860.1300 : Nature of the Residue: Poultry

 860.1340 : Residue Analytical Method: Livestock Commodi ties
 860.1380: Storage Stability
 860:1480: Meat/Milk/Poultry /Eggs : Ruminants
 860.1900: Field Accumulation in Rotational Crops Tables describing the rationale for requiring these studies are attached to this document. In addition, once the rotational crop studies have been completed product labels should be modified to include appropriate plant

- back intervals. The registrants should also certify that the levels of the impurities of concern have not changed since the most recent risk assessment that considered the cancer risk to these toxic impurities.Page 12 of 22

References Bradman A, et al. 2007. Pesticides and their metabolites in the homes and urine of farmworker children living in the Salinas Valley , CA. J Expo Sci Environ Epidemiol 17:331

- 349. FR Vol. 70 No. 143 (07/27/05) pp 43408

- 43410, DCPA; Order to Amend to Terminate Uses

. Gray , Jr. LE, et al. Perinatal Exposure to the Phthalates DEHP, BBP, and DINP, but Not DEP, DMP, or DOTP, Alters Sexual Differentiation of the Male Rat. Toxicol. Sci. (2000) 58(2): 350

- 365 doi:10.1093/toxsci/58.2.350 Gunier RB, et al. 2011

. Determinants of Agricultural Pesticide Concentrations in Carpet Dust. Environ Health Perspect doi:10.1289/ehp.1002532 (accessed March 3, 2011) Harnl y ME, et al. 2009. Pesticides in dust from homes in an agricultural area. Environ Sci Technol 43:8767

- 8774. Nuckols JR, et al . 2007. Linkage of the California Pesticide Use Reporting Datab ase with spatial land use data for exposure assessment. Environ Health Perspect 115:684

- 689. Nuckols JR, Riggs PD, Gunier RB, Ward MH 2008. Geographic

- based prediction of agricultural pesticides in household carpet dust in the central valley of California

. Epidemiology 19:S320.

U.S. EPA . 1998b. Reregistration Eligibility Decision (RED): DCPA . EPA 738

- R

- 98

- 005. November 1998. Special Review and Reregistration Division, Office of Pesticide Programs. Washington, D.C. U.S.A. Available at: http://www .epa.gov/oppsrrd1/REDs/0270red.pdf (accessed January

28 , 20 11 )
U.S. EPA . 2008 a
. Health Effects Support Document for Dacthal Degradates: Tetrachloroterephthalic Acid (TPA) and Monomethyl Tetrachloroterephthalic Acid (MTP). EPA

- 822

-R

- 08

- 005 . May , 2008. Health and Ecological Criteria Division. Office of Water. Washington, D.C. U.S.A. Available at: http://www.epa.gov/safewater/ccl/pdfs/reg_determine2/healtheffects_ccl2

- reg2_dacthaldegradates.pdf (accessed Febr uary 2 8 , 20 11 )

OPP Memoranda Citations

Author DP Barcode/

Record No. Date Title Winfield, S. D386640 3/1/11 DCPA: Review of Human Incidents Ratnayake , S., et al. N/A 1/20/11 BEAD Chemical Profile for Registration Review: DCPA (07870I)
N/A N/A 8/18/10 EPA Screening Level Estimate of Agricultural Uses (SLUA) (8/18/10) N/A N/A 8/10/10 EPA Analysis of California DPR Pesticide Usage Data (Page 13 of 22

Author DP Barcode/

Record No. Date Title

Dole , T. D 303994 6/9/04 2nd Revised Drinking Water and Aggregate Human Health Risk Assessment for Chlorthal dimethyl (DCPA) and the metabolite tetrachloroterephthalic acid (TPA) Farwell, K. D303156 5/25/04 TPA (tetrachloroterephthalic acid)

- metabolite of DCPA (Dacthal). Evaluation of Potential for Carcinogenicity. Farwell, K. and Abdel

Saheb, I. TXR No.

0052 585 5/25/04 TPA (tetrachloroterephthalic acid)

- metabolite of DCPA (Dacthal). Report of the Metabolism Assessment Review Committee Dole, T., et. al. D281320 7/8/02 HED Human Health Risk Assessment For DCPA to Support New Uses on California Parsley and Other Minor Crops (D281320, 7/8/02) Hazel, W. D280398 6/14/02 PP#0E3883 and PP#2E6442. IR

- 4 Petitions for Tolerances and Proposals. Review of Analytical Chemistry and Residue Data. Dole, T. D283509 6/10/02 Occupational and Residential Risk Assessment to Support Request for Establishment of Tolerance for Chlorthal

- Dimethyl (DCPA) on Minor Crops. Taylor, L., and Rinde, E. TXR No.

0050123 2/10/95 Carcinogenicity Peer Revie w of DCPA (Dimethyl tetrachloroterephthalate or Dacthal)for meetings on June 29 and Nov. 16, 1994. Linda Taylor and Esther Rinde.Page 14 of 22

Attachments Chemical Identity Table 1. Chemical Identity Common Name DCPA Other Names Chlorthal dimethyl; CAS Name: dimethyl 2,3,5,6

- tetrachloro

- 1,4

- benzenedicarboxylate ; IUPAC Name: dimethyl tetrachloroterephthalate PC Code 078701 1861

- 32

- 1 Case No. 0720 Chemical Structure

Metabolites/Degradates of Concern Name mo nomethyltetrachloroterephthalate (MTP) CAS registry number 887

- 54

- 7 Chemical Structure

Name tetrachloroterephthalic acid (TCP or TPA) CAS registry number 2136

- 79

- 0 Chemical Structure

Table 2. Summary of US and International Residue Limits Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 180.185(a) Cantaloupe 1.0 1.0 None None Garlic 1.0 1.0 None None Ginseng 2.0 None None None Horseradish 2.0 None None NonePage 15 of 22

Table 2. Summary of US and International Residue Limits Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Muskmelon 1.0 Honeydew melon: 1.0 None None Onion, bulb 1.0 1.0 None None Onion, green 1.0 None None None Straw berry 2.0 2.0 None None Tomato 1.0 1.0 None None Vegetable, brassica, leafy, group 5
5.0 B roccoli , Brussels Sprouts, Cabbages, C auliflower : 1 .0 Collards, Kale: 2 Mustard Greens : 5 None None

Watermelon 1.0 1.0 None None 180.185(c) (tolerances with regional registration) Radish, roots 2.0 None None None Radish, tops 15.0 None None None 180.185(d) (inadvertent tolerances) 3 Basil, dried leaves 20.0 None None None Basil, fresh leaves 5.0 None None None Bean, dry 2.0 None None None Bean, mung, seed 2.0 None None None Bean, snap, succulent 2.0 2.0 None None Celeriac 2.0 None None None Chicory, roots 2.0 None None None Chicory, tops 5.0 None None None Chive 5.0 None None None Coriander, leaves 5.0 None None None Corn, field, forage 0.4 None None None Corn, field, grain 0.05 None None None Corn, field, stover 0.4 None None None Corn, pop, forage 0.4 None None None Corn, pop, grain 0.05 None None None Corn, pop, stover 0.4 None None None Corn, sweet, forage 0.4 None None None Corn, sweet, kernel plus cob with husks removed 0.05 None None None Corn, sweet, stover 0.4 None None None Cotton, undelinted seed 0.2 None None None Cucumber 1.0 1.0 None None Dill 5.0 None None None Eggplant 1.0 1.0 None None Lettuce 2.0 2.0 None None Marjoram 5.0 None None None Parsley, dried leaves 20.0 None None None Parsley, leaves 5.0 None None None Pea, blackeyed, seed 2.0 2.0 None None Pepper 2.0 2.0 None None Pimento 2.0 2.0 None None Potato 2.0 2.0 None None Radicchio 5.0 None None None Radish, oriental, roots 2.0 None None NonePage 16 of 22

Table 2. Summary of US and International Residue Limits Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Radish, oriental, tops 2.0 None None None Rutabaga 2.0 None None None Soy bean 2.0 None None None Squash, summer 1.0 1.0 None None Squash, winter 1.0 None None None Sweet potato 2.0 2.0 None None Turnip, roots 2.0 2 None None Turnip, tops 5.0 5 None None Yam , true, tuber 2.0 2 None None 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 Canada does not distinguish maximum residue limits in their maximum residue limit regulations. Therefore the Canadian limits included in this section do not specifically refer to inadvertent residues.

Table 3. Summary of Revised Maximum Reasonable Dietary Burden for DCPA Feed Commodity Feedstuff Ty pe % Dry

Matter Percent in

Diet Tolerance

Level Max

Contribution Beef Cattle (R=15%; CC=80%; PC=5%) Corn Forage R 40 15 0.4 0.15 Corn Grain CC 88 50 0.05 0.028 Processed Potato Waste CC 15 30 2 4 Soy bean Seed PC 89 5 2 0.11 Total NA NA 100 NA 4.29 Dairy Cattle (R=45%; CC=45%; PC10%) Corn Forage R 40 15 0.4 0.15 Turnip Tops R 30 30 5 5 Turnip Roots CC 15 10 2 1.33 Processed Potato Waste CC 15 10 2 1.33 Corn Grain CC 88 25 0.05 0.014 Soy bean Seed PC 89 10 2 0.22 Total NA NA 100 NA 8.0 6 Poultry (CC=75

- 80%; PC=20

- 25%) Corn Grain CC NA 0 80 0.05 0.04 Soy bean Seed PC 20 2 0.4 Total 0.44 Hogs (CC=80

- 85%; PC=15

- 20%) Corn Grain CC 0 80 0.05 0.04 Soy bean Seed PC 20 2 0.4 Total NA NA 100 NA 0.44Page 17 of 22

Rationale for Requiring a Poultry Nature of the Residue Study
Guideline Number: 860.1300 Study Title: Nature of the Residue, Livestock (Poultry) Rationale for Requiring the Data This study provides essential information on the potential transfer and bioconcentration of residues in poultry meat and eggs for pesticides applied to feed items. Many pesticides undergo change during or after livestock consume treated feed. The composition of the terminal residue must be determined before complete residue d etection methodology and residue quantification data can be developed. The study may help to validate the poultry magnitude of residue data previously submitted if no new residues of concern are identified. The requested poultry nature of the residue study will need supporting storage stability data for all DCPA residues of concern, unless the samples from the feeding study are analyzed within six months of collection. Practical Utility of the Data How did the Agency make its re
- registration decision without these data? In order to make its reregistration decision, the Agency assumed poultry would have similar types of residues as cattle and goats.
How will the data be used? The data will be u sed to provide a full characterization of the DC P A residue profile. The submission will provide the necessary data to set tolerances for livestock commodities. These data may also result in a change in how dietary risks are quantified.

Rationale for Requiring an Independent Laboratory Validation for a Livestock Residue Analytical Method
Guideline Number: 860.1340 Study Title: Residue Analytical Methods (enforcement analytical method for livestock) Rationale for Requiring the Data One of the analytical methods submitted by the registrant must be suitable for use by various Federal and State enforcement agencies. The Food and Drug Administration (FDA) collects these methods and then publishes them to be used for tolerance enforcement purposes. The registrant has submitted a method for determining residues of DCPA and its metabolites that may be suitable but must be tested by an independent laboratory to ensure that it is useful. Practical Utility of the Data How will the data be used? EPA would review the independent laboratory validation of the submitted method and determine its suitability as an enforcement method. If suitable, EPA would forward the method to FDA. The enforcement analytical methods are published by FDA and are available to all regulatory laboratories for use in monitoring the specific pesticide concentrations in foods and feeds. They are a necessary tool for tolerance enforcement and residue monitoring and, as such are essential in the efforts to ensure a safe food supply for the consumer.Page 18 of 22

Rationale for Requiring Cattle M agnitude of Residue Study
Guideline Number: 860.1480 Study Title: Magnitude of the Residue (Cattle Feeding Study) Rationale for Requiring the Data A new ruminant feeding study is required to determine whether tolerances are needed (and if so the appropriate tolerance levels) for milk and meat. The requested ruminant feeding study will need supporting storage stability data for all DCPA residues of concern, unless the samples from the feeding study are analyzed within 30 days of collection. Practi cal Utility of the Data How did the Agency make its re
- registration decision without these data? The Agency has made conservative assumptions within the dietary assessment to account for the lack of magnitude of the residue (MOR) data from the cattle feeding studies. Residue estimates based on the metabolism studies were included to account for potential exposure to DCPA and it metabolites in meat and milk from ruminants. However, these data are needed to ensure that the correct assumptions were made.
How will the data be used? The data will be used to provide a full characterization of the DCPA residue profile. The submission of livestock MOR data would provide the necessary data to determine if tolerances are needed for livestock commodities and if neces sary, to set the appropriate tolerance levels. How could the data impact the Agency’s future decision
- making? The submission of MOR data would provide the necessary data to set tolerances for livestock commodities. These data may also result in a change i n how dietary risks are quantified.Page 19 of 22

Rationale for Requiring Field Accumulation in Rotational Crops Study
Guideline Number: 860.1900 Study Title: Field Accumulation in Rotational Crops Rationale for Requiring the Data A rotational crop use is any field

- ve getable crop use or any other site use on which it is reasonably foreseeable that any food or feed crop may be planted after harvest of a treated crop. The purpose of field accumulation in rotational crop studies is to determine the amount of pesticide residue uptake into rotational crops. The study uses a typical end

-use product applied to a field plot. Results of these studies are used to determine whether residues occur in rotational crops grown under actual field conditions. Based on these data, appropriate crop rotation restrictions (time from application to planting of rotational crop) may be established and the need for tolerances on the rotated crops determined. Carrot roots and tops, corn fodder and silage, oat forage, and turnip tops from plants sowed at a 1

-year plantback interval in soil treated at half the maximum application rate bore quantifiable residues in one or more samples. These data indicate that tolerances are needed for residues of DCPA and metabolites in some crops if they are rotated to fields that have been treated at even half the maximum seasonal label rate. The petitioner/registrant has not proposed any restrictions that obviate the need for rotational crop tolerances. Large

- scale rotational crop field trials are required to determine the appropriate tolerance levels for rotated crop commodities. The scope of the required tests is dependent upon the petitioner’s/registrant's intent with respect to the crops to be allowed in rotation and the desired plantback interval(s) for these crops. Any crop without a registered use, for which the petitioner/registrant wishes to allow rotation, requires field trial data to determine a suitable tolerance level. A crop group approach, requiring data on representative commoditi es, may be appropriate if several crops within a group are to be rotated. For individual crops, the standard number of trials needed to support direct crop treatment tolerances are required, e.g., 20 trials for wheat. Practical Utility of the Data How did the Agency make its re
- registration decision without these data? Since the data were lacking, the Agency was not able to evaluate risks for rotational crops.
How will the data be used? The data will be used to provide a full characterization of the DC P A residue profile. The submission of these data would provide the necessary information to determine if tolerances are needed for rotated crops and if so, to set the appropriate tolerance levels. These data may also result in a change in how di etary risks are quantified. How could the data impact the Agency’s future decision
- making? The submission of these data would allow the Agency determine if tolerances are necessary for rotational crops and if so, to set the appropriate tolerances. The previously submitted confined and limited field rotational crop studies have shown potential residue uptake into rotated crops. If residues are detected in crops without established tolerances, these crops may be seized by the Food and Drug Administration (FDA). Accurate rotational crop tolerances protect farmers from inappropriate crop seizures.Page 20 of 22

Ratio nale for Requiring a 28
- day Subchronic Toxicity Study
Guideline Number: 870.3465 Study Title: Subchronic Inhalation Toxicity Study Rationale for Requiring the Data This data requirement is conditionally required under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non

- food uses). This study is required for DCPA because workers can potentially be exposed to DCPA via the i nhalation route of exposure. DCPA is in toxicity category IV for inhalation exposure and is a mild irritant to the eyes and skin and is not a skin sensitizer. Practical Utility of the Data How will the data be used? This study can be used to select endpoints and doses for use in exposure assessment for workers by the inhalation route of exposure. How could the data impact the Agency's future decision
- making? This study will be used in a worker occupational exposure assessment. This study was requested in the previous risk assessment.
Rationale for Requiring a Comparative Thyroid Study
Guideline Number: 870.3700SS (Special Study) Study Title: Comparative Thyroid Study Rationale for Requiring the Data Thyroid toxicity with treatment with DCPA has been observed in studies with adult animals, but no such data exist for developmental effects of DCPA on the thyroid and thyroid hormones of young animals. Practical Utility of the Data How will the data be used? The thyroid and thyroid hormones are adversely affected by treatment with DCPA, but data are lacking with which to estimate developmental risks associated with this toxicity. The data may provide a dose and endpoint for use in the assessment of risks for children and will play a role in the registration review decision. How could the data impact the Agency’s future decision
- making? If the study indicates there is a special vulnerability to children from DCPA, a new toxicity endpoint will be incorporated into the risk assessment for children.Page 21 of 22

Rationale for Requiring The Neurotoxicity Battery

Guideline Number: 870.6200 Study Title : Neurotoxicity Battery (Acute and Subchronic Studies) Rationale for Requiring the Data The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential adverse effects on the nervous system from exposure to pesticide chemicals. The Agency believes that the guideline studies are inadequate in their assessment of beh avioral effects and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize these potential effects more fully, a battery of more sensitive testing is required. The objective of this neurotoxicity battery testing is to evaluate the incidence and severity of the functional and/or behavioral effects, the level of motor activity, and the histopathology of the nervous system. The acute neurotoxicity study is required to detect possib le effects resulting from a single exposure. The subchronic neurotoxicity study is intended to detect possible effects resulting from repeated or long

term exposures. Neurotoxicity was not detected in the toxicity studies with DCPA. Practical Utility of

the Data How will the data be used? The acute and subchronic neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the nervous system from pesticide exposure. These studies can provide data on a wide range of function al tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system and can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. How could the data impact the Agency's future decision
- making? If the acute or subchronic neurotoxicity studies show that DCPA poses either a greater or a diminished risk than th at given in the previous risk assessment, the risk assessment may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have these data, a 10X database uncertainty factor may be applied when con ducting a risk assessment using the currently available studies.Page 22 of 22

Rationale for Requiring an Immunotoxicity Study
Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non

- food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential immunotoxici ty. These data will be used in combination with data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential immunotoxic effects. Practical Utility of the Data How will the data be used? These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demons trated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8

- tetrachlorodibenzo

-p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). How could the data impact the Agency's future decision
- making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have these data, a 10X databas e uncertainty factor may be applied for conducting a risk assessment from the available studies.APPENDIX TO DCP A SCOPING DOCUMENT

Page 1 of 1 Discussion on Toxic Impurities The manufacturing process of DCPA produces several contaminants known to be of significant toxicological concern , including hexachlorobenzene (HCB) and congeners (structurall y related chemicals) of pol yh alogenated dibenzo

- p - dioxins/dibenzofurans (dioxins/furans). Carcinogenic risk was assessed for dietary exposure to HCB and dioxin/furans using cancer potency factors of 1.02 (mg/kg/day) - 1 and 1 x 10 5 , respectively. Estimated dietary risks were negligible and below the level of concern. In addition, cancer risk from these contaminants was assessed for occupational exposure and was below the level of concern.